<p>Huntington’s disease (HD) is a movement disorder commonly recognized as being neurodegenerative. An increasing number of studies also show primary HD dysfunction in multiple tissues, consistent with the widespread expression of the mutated <i>huntingtin</i> gene. Studies of HD skeletal muscle have revealed membrane hyperexcitability and prolonged action potentials due to Cl^– and K⁺ channel dysfunction as well as decreased Ca²⁺ release from the sarcoplasmic reticulum (SR) due to ryanodine receptor dysfunction. However, neither mechanism alone explains HD skeletal muscle function. To address this, we simultaneously recorded action potentials and SR Ca²⁺ release in model HD muscle and quantitatively linked the concerted mechanism to force generation. We discovered that the reduced SR Ca²⁺ release does not cause weakness in model HD muscle as expected because of the prolonged SR Ca²⁺ release (due to wider action potentials) and altered expression of Ca²⁺-binding proteins. The resulting integrated mechanism helps explains the surprisingly normal specific twitch force in model HD muscle and reveals a precarious balance that we show begins to disintegrate under very mild repetitive stimulation. The interplay of pathways also explains the resistance to myotonia in model HD muscle despite the substantial reduction in Cl⁻ current. By examining a concerted multi-molecular mechanism, we are able to understand tissue-level function in model HD muscle. This detailed study of twitch responses lays the foundation to examine the more complex integration of pathways during repetitive activity in HD muscle as well as in other normal and disease states that would benefit from the multi-molecular approach.</p>